The present disclosure generally relates to dosing units for infusion pump devices, infusion pump devices with such dosing units, and methods for operating such infusion pump devices.
Devices for the automated release of liquid medicaments are normally used with patients who have a continuous and, in the course of the day, varying need of a liquid medicine administered by infusion. Specific applications are, for example, certain pain therapies, cancer therapies and the treatment of diabetes mellitus, in which computer controlled infusion pump devices are used. Such devices are particularly useful for ambulatory therapy and are generally carried attached on or near the body of a patient. The medicine reservoir often comprises medicine supply sufficient for one or several days. The liquid medicament is supplied to the patient's body from the medicine reservoir through an infusion cannula or an injection needle.
Ambulatory infusion pump devices are typically of the syringe driver type as schematically described in FIG. 1(a). The liquid medicament to be administered to the patient 32 is stored in a cylinder 14 of the dosing unit 10, comprising the complete reservoir 11 of liquid medicament of the infusion pump device. The liquid medicament is conveyed to the body of the patient 32 by unidirectionally displacing a piston 16 within the cylinder via a piston shaft 18 or threaded spindle. An outlet 25 is fluidly connected 26 to infusion tubing 28, which on its other end is fluidly connected to an infusion site interface 30 attached to the body. For safety reasons, it is generally preferred to regularly replace any parts that come into contact with liquid medicament, such as for example the infusion tubing. The reservoir is, in most cases, a single use cartridge that may be provided prefilled, or may be provided empty and is filled by the user.
A number of drawbacks of such syringe-type pump designs are known in the art. In particular, such pump devices have a limited precision, because very small volumes, typically in the nanoliter range, are pumped out of a cartridge having an overall volume in the range of milliliters. To achieve precise dosing of the liquid medicament, it is necessary to very precisely displace the piston. Even small deviations can lead to over dosing or under dosing, and the forces needed to actuate the piston are comparably high due to the friction between the walls of the glass cartridge and the sealing of the piston and the material hysteresis of the sealing. This leads to demanding requirements for the drive system and the mechanical parts involved, as well as the control unit of the pump. As a consequence, such infusion pump devices are expensive.
Another problem is the lower limit of the length of such an infusion pump device. The complete supply of liquid medicament has to be stored in the cartridge acting as the pump cylinder. The cross-sectional area of the piston has to be below a certain limit, for precision reasons and in order to limit the device thickness, which is known to be a particularly critical dimension with respect to comfort and discreetness during application. The minimum overall length of the device is then essentially given by the resulting minimum length of the cylinder, which is detrimental to the provision of compact infusion pumps. Particularly in self-administration of medicaments, for example insulin, the patients using the medicament in question and administering it themselves by an infusion pump are increasingly emphasizing convenience and discretion which restricts the acceptable size and weight of such devices so not be evident through clothing and to be carried as comfortably as possible.
In an alternative approach, a separate dosing unit is provided downstream from the liquid medicament reservoir. Since the primary reservoir does not have to fulfill additional functions, its dimensions can be optimized in view of the compactness of the infusion pump device. Such a dosing unit may for example comprise a micro piston pump with small dimensions that retrieves liquid medicament from the larger primary reservoir, e.g., a collapsible reservoir, and conveys the liquid medicament to the body of the patient. Such pumps are generally full-stroke pumps, where the cavity of a membrane pump or the cylinder of a piston pump is always completely emptied. Hence, the inner volume of the pump must correspond to the smallest volume increment that has to be delivered, typically in the nanoliter range. While several designs for such dosing units are known in the art, they are rather complex, expensive and critical with respect to large scale manufacture, since they integrate a number of functional components, in particular metering components and valves and are frequently made from materials which are costly and/or critical in production and processing, such as silicon. Since it is preferable to realize all parts that come into contact with the liquid medicament, including the pump, as disposable elements that are replaced after a certain time, such pump designs are costly. Thus advantageously all expensive parts of a dosing unit should be reusable while the disposable parts should be producible at lower costs.
One implantable infusion pump device, with an primary reservoir in the form of an elastic bellow, a conduit fluidly connecting the conduit to a variable-volume chamber in the form of an elastic bellow, a valve with which the conduit can be opened and closed, and a downstream catheter fluidly connecting the variable-volume chamber with the infusion site is known. The volume of the variable-volume chamber is considerably smaller than the volume of the primary reservoir. Two limiters are placed in such a way as to limit the variation in volume of the variable-volume chamber, between a lower volume limit and an upper volume limit. In a first step, the elastic reservoir is filled by a syringe, the valve being closed. Starting from a certain degree of extension of the elastic reservoir, the restoring force of the latter is such that the liquid can be expelled into the conduit. When the valve is open, the liquid is conveyed toward the variable-volume chamber, driven by the pressure differential in the primary reservoir. As soon as the upper volume limit of the variable-volume chamber is reached, the valve closes and the liquid is conveyed by the restoring force of the elastic variable-volume chamber into the downstream catheter and toward the site to be treated. When the variable-volume chamber reaches the lower volume limit, liquid is no longer expelled from it. At the end of a time interval, determined as a function of the desired dosage rate, the valve opens again and the process as described above is continuously repeated. In other words, the primary reservoir of the device acts as a spring force driven syringe pump with constant dosage rate. The administration rate is controlled by the time intervals between temporarily opening the valve, each corresponding to a full stroke of the spring force driven secondary piston pump in the form of the elastic variable-volume chamber, and the positions of the two limiters, which regulate the volume per stroke.
Although the dosage precision is said to be high in such a device, this precision is based on a statistical average. The volume of single administered portions cannot be adjusted, only the average administration rate can be changed. As a result such a device cannot be used for dosage regimes as necessary for the treatment of diabetes mellitus, in which the administered dosage of each single portion of insulin should be adjustable to the current need of the patient.
The use of such a device is even potentially dangerous, particularly when using highly potent drugs such as insulin. Although it is suggested to use controllable valves in both conduits in order to avoid the known problem of the temporary bypass between the primary reservoir and the catheter during filling of the variable-volume chamber, a malfunction of the valves can lead to an unrestricted and uncontrolled flow of liquid medicament from the primary reservoir directly to the catheter. The possibility of such an event has to be avoided at all cost.
In yet another approach, the cylinder of the piston pump of the dosing unit acts as a secondary reservoir and can hold an intermediate amount of liquid medicament. The pump retrieves liquid medicament from the primary reservoir and conveys the medicament in variable doses. This compromise allows reducing the overall device dimensions while at the same time doses of variable quantities can be provided.
A device following such an approach has a flexible secondary reservoir with an adjustable volume that is fluidly connected by a first conduit to a flexible primary reservoir and by a second conduit to an infusion catheter. The volume of the second reservoir, e.g., 100 μl, is chosen between the volume of the primary reservoir, e.g., 10 ml, and the volume of the smallest intended dosage portion, e.g., 1 μl. A valve is arranged in each conduit for controlling the correct flow of liquids during the filling of the secondary reservoir and during the dosing. The valves are either check valves, which allow the flow of liquid only in the foreseen direction, from the primary reservoir to the secondary reservoir during filling and from the secondary reservoir to the catheter during dosing, or electrically controlled valves that are opened and closed as necessary for achieving such a function.
The use of such a device is again potentially dangerous, particularly when using highly potent drugs such as insulin. When check valves are applied, any over pressure in the primary reservoir will directly lead to an unrestricted and uncontrolled flow of liquid medicament from the primary reservoir via the second chamber to the infusion site. The same is the case if for some reason electrically controlled valves malfunction and are both open at the same time. Since this problem is known, the pressure inside the primary reservoir must in no case be higher than environmental pressure. However, obviously such a precondition for a save operation of the device cannot be guaranteed. Particularly when for some reason a certain amount of air is present in the primary reservoir, any increase of environmental temperature of decrease of environmental pressure will inevitably lead to an overpressure in the primary reservoir.
One embodiment of such a type of infusion pump device is schematically depicted in FIG. 1(b). A 4/3 or 3/3 way valve 35 is arranged at a front end of the cylinder 14 of the dosing unit 12. The valve is realized as a rotatable cylinder head acting as a valve member, which interacts with a fixed cylinder tube acting as the valve seat. A piston 16 in the cylinder of the dosing unit can be bidirectionally displaced along the cylinder axis by a drive system 20. During the refill mode, when the dosing unit retracts the piston and sucks liquid medicament from the primary reservoir 11 into the cylinder 14, an inlet conduit 24 fluidly connected to the primary reservoir is fluidly connected to the cylinder and an outlet conduit 25 fluidly connected 26 to the infusing tubing 28 is disconnected from the dosing unit. During the pumping mode, when liquid medicament is conveyed from the secondary reservoir 15 in the cylinder of the dosing unit to the subcutaneous tissue of the patient 32, the cylinder 14 of the dosing unit is fluidly connected to the outlet conduit 25 establishing a fluid connection to the body of the patient while the inlet conduit 24 is disconnected from the dosing unit.
Alternatively, a rotatable cylinder can act as the valve member mounted in a fixed valve seat. An embodiment of the latter variant is where the actuator of the piston indirectly actuates the valve member by rotating the cylinder frictionally connected to the piston.
For precise metering, it is necessary to either use a pump motor that can be very precisely controlled, for example a stepper motor, or to monitor the actual position of the piston.
One method discloses monitoring the position of a displaceable stopper in an insulin ampoule. In one approach, the displaceable stopper is equipped with markers, e.g., visual markers, that can be detected by sensors arranged along the ampoule. In order to precisely determine the position of the stopper, a large number of sensors are necessary. The cylinder wall has to be at least partially transparent so that the sensors can see the visual markers.
One known syringe-like injection pen device has a piston rod provided with optical markings, namely numbers, which can be visually detected by a user through an aperture in the housing. By reading the number in the aperture, the user can monitor the position of the piston in the syringe, for determining the administered or remaining dose. For an automated system, this approach is not precise enough.
One known infusion pump device with a cylinder pump has a longitudinally displaceable piston with a split piston shaft that connects the piston head with a threaded nut. The piston cannot rotate. The threaded nut interacts with a rotating threaded drive shaft, thereby translating the rotation of the drive shaft into a linear displacement of the piston head. One or more detectable features such as magnetic or optical markers can be arranged on the piston shaft, which can be detected by a corresponding sensor for determining the linear position of the marker and thus of the piston head. The precision of the position determination is restricted by the precision of the determination of the linear position of the marker.
One known cylinder pump discloses a wheel interacting with the piston shaft during the linear displacement of the piston. The linear displacement is translated into a rotation of the wheel and further to a rotation of a second wheel with a multitude of radial lines. This wheel is illuminated through a transparent plate that is also provided with a multitude of radial lines. A single sensor detects the impinging light. In addition to the complex construction of such a device, with a multitude of moving parts, the achievable precision is inherently reduced by frictional slip between wheel and piston shaft.
In a worst case pump failure scenario, the whole content of the reservoir can be inadvertently administered because of continuous and unintended operation of a pump unit, e.g., due to a fault in the drive control circuitry. Although, the maximum dosing volume in the secondary reservoir is considerably smaller than the complete content of a cartridge of a conventional syringe pump, for example by a factor of 25, the liquid medicaments that are administered by liquid infusion pump devices are generally highly effective and the inadvertent administration of the complete secondary reservoir is undesirable.
Another issue of infusion pump devices can be air bubbles in the fluidic system, particularly in the pump system, but also in other components, such as the container. If air bubbles remain in the fluidic system, they may be administered instead of the liquid medicament leading to undesired dosing errors. Furthermore, the administration of air into a patient's body should be generally avoided for medical reasons.
One problem resulting from air in the fluidic system is the reduced stiffness of the fluidic system, due to the high compressibility of gases in relation to liquids such as water. This impedes detection of blockages or occlusions in the fluidic system by monitoring the fluidic pressure.
A syringe type-pump system for fluid dispensing arrays for multiwell plates is known. The syringe pump comprises a cylinder and a movable plunger, a first inlet conduit fluidly connected to a fluid reservoir, and a second outlet conduit connected toward a dispensing tip. A three-way port valve alternatingly connects the first conduit and the second conduit to the pump cylinder for refilling and for dispensing, respectively. The syringes are mounted vertically, in order to allow air bubbles in the pump cylinder to rise upward toward the exit port to the second conduit, so that they can be removed from the fluid system during the priming procedure, by conveying them through the second conduit and out of the dispensing tip. In order to prevent air bubbles that have been drawn into the pump cylinder volume during a first filling step of the priming procedure from accumulating in the dead volume between pump cylinder and valve and reentering again into the cylinder volume in the next filling step of the priming sequence, the dead volume is reduced to a minimum. For this the length of the conduit between the valve and the cylinder is minimized. Thus less air bubbles can accumulate in the dead volume. In some embodiments, special valves are used with a valve member that provides two different internal channels, one channel connecting the first conduit to the cylinder in the first state and the second channel connecting the second conduit to the cylinder. Thus air bubbles remaining in the second channel after the first priming cycle of drawing liquid into cylinder and expelling the liquid through the dispensing tip are not drawn again into the cylinder during the second priming cycle.
The priming of this syringe pump comprises at least two priming cycles of filling the pump cylinder and expunging the liquid through the outlet conduit. The priming of the disclosed pump functions only if the pump is in the intended orientation, since the correct path of air bubbles during the priming procedure is given by the direction of the buoyancy force in combination with the geometry of the pump elements.
When environmental atmospheric pressure changes, especially drops, within a short time, for example due to fast changes in height when travelling in elevators or mountainous areas, or due to cabin pressurization in air planes, air present in the dosing unit or the infusion tubing will expand. As a result an additional dose of liquid medicament is expelled from the fluid system into the body of the patient. A similar effect may occur in case of a change in temperature.
Since the health of a patient is of primary importance and needs to be protected, there is a need to improve the safety level of infusion pump devices by providing an improved dosing unit that has a dosing unit that minimizes dosing errors of various causes, minimizes the possible maximum dosing error, minimizes the amount of air in the fluidic system during filling, and allows a precise metering of liquid medicament that is reliable and producible with high quality at low costs in a large-scale manufacture.